The atrophic (dry) form of age-related macular degeneration (AMD), which is the most common form of the disease, is largely untreatable. Accumulating evidence suggests that dysfunction and loss of retinal pigment epithelial (RPE) cells plays an important role in the pathophysiology of AMD. Efforts have therefore been made to A) develop agents that promote RPE health and survival and B) develop cell transplantation-based approaches to replace the dysfunctional and lost RPE cells. In this application we propose to take complementary High Throughput Screening (HCS) and High Content Screening (HCS) approaches to identify small molecules that promote the survival of human stem cell-derived RPE cells exposed to oxidative stress (Specific Aim 1) and molecules that promote the differentiation of stem cells towards an RPE phenotype (Specific Aim 2). Given that oxidative stress has been implicated in AMD, the molecules identified in Aim 1 will hopefully serve as lead molecules for the development of cytoprotective approaches for dry AMD therapy. And the molecules identified in Aim 2 will hopefully aid in the development of improved cell-based treatment approaches for dry AMD. In addition, the molecules from both aims will also serve as molecular probes that will be useful in study of the mechanisms that determine RPE differentiation and that modulate the RPE cell's response to oxidative stress.